Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2)

Gille, Hendrik; Kowalski, Joe; Li, Bing; LeCouter, Jennifer; Moffat, Barbara; Zioncheck, Thomas F.; Pelletier, Nicolas; Ferrara, Napoleone

doi:10.1074/jbc.m002016200

Cited by 537 publications

(199 citation statements)

References 50 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…More importantly, the results suggest that activation of MAPK by VEGFR-2 is not associated with endothelial cell proliferation. Similar results using different endothelial systems have shown that activation of VEGFR-1 is not associated with endothelial cell proliferation (De Vries et al, 1992;Keyt et al, 1996;Fong et al, 1999;Rahimi et al, 2000;Gille et al, 2001). VEGFR-1 activation even in some nonendothelial cells, such as hepatic stellate cells, is reported to attenuate contraction of these cells without effecting DNA synthesis (Mashiba et al, 1999).…”

Section: Discussionsupporting

confidence: 54%

“…Although VEGFR-1 and VEGFR-2 are structurally highly similar, their angiogenic signal transduction appears to differ drastically from each other. Activation of VEGFR-2 positively regulates angiogenesis (Breier 2000;Yancopoulos et al, 2000;Gille et al, 2001) and it is highly autophosphorylated in response to ligand stimulation (Waltenberger et al, 1994;Shalaby et al, 1995;Rahimi et al, 2000). VEGFR-1 is poorly autophosphorylated in response to ligand stimulation in endothelial cells and appears to regulate angiogenesis negatively (Waltenberger et al, 1994;Fong et al, 1999;Rahimi et al, 2000;Kearney et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Selective activation of VEGFR-1 is not associated with endothelial cell migration, intracellular calcium release and angiogenesis in vitro Activation of VEGFR-1 is not associated with endothelial cell proliferation (De Vries et al, 1992;Keyt et al, 1996;Fong et al, 1999;Rahimi et al, 2000;Gille et al, 2001). To test whether VEGFR-1 activation modulates other cellular functions, we subjected cells expressing CTR to cell migration, intracellular calcium release and in vitro angiogenesis.…”

Section: Vegfr-1 Is Devoid Of Ligand-dependent Autophosphorylation Inmentioning

confidence: 99%

See 2 more Smart Citations

Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation

et al. 2004

View full text Add to dashboard Cite

VEGFR-1 is devoid of ligand-dependent tyrosine autophosphorylation and its activation is not associated with proliferation of endothelial cells. The molecular mechanism responsible for this characteristic of VEGFR-1 is not known. In this study, we show that VEGFR-1 is devoid of ligand-dependent downregulation and failed to stimulate intracellular calcium release, cell migration and angiogenesis in vitro. To understand the molecular mechanisms responsible for the poor tyrosine autophosphorylation of VEGFR-1, we have either deleted the carboxyl terminus of VEGFR-1 or exchanged it with the carboxyl terminus of VEGFR-2. The deletion of carboxyl terminus of VEGFR-1 did not reverse its defective ligand-dependent autophosphorylation. The carboxyl terminus-swapped VEGFR-1, however, displayed ligand-dependent autophosphorylation, downregulation and also conveyed strong mitogenic responses. Thus, the carboxyl tail of VEGFR-1 restrains the ligand-dependent kinase activation and downregulation of VEGFR-1 and its ability to convey the angiogenic responses in endothelial cells.

show abstract

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Vegfr-1 Is Devoid Of Ligand-dependent Autophosphorylation Inmentioning

confidence: 99%

See 1 more Smart Citation

Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation

et al. 2004

View full text Add to dashboard Cite

show abstract

“…The different phenotypes of these VEGFR Ϫ homozygous mice suggest that VEGFR-2 is the major positive signal transducer, whereas VEGFR-1 has a negative regulatory role in angiogenesis early in embryogenesis. A VEGFR-2-selective VEGF mutant or VEGF-E (a VEGFR-2-specific ligand) is able to induce vascular permeability to an extent indistinguishable from that of wildtype VEGF 165 , whereas a VEGFR-1-selective VEGF mutant or PlGF (a VEGFR-1-specific ligand) has little or no direct permeability-enhancing activity (10,11,14,19). Therefore, not only physiological angiogenesis but also the enhancement of vascular permeability have been considered to be mediated through VEGFR-2 (but not VEGFR-1) activation.…”

Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 99%

A Novel Snake Venom Vascular Endothelial Growth Factor (VEGF) Predominantly Induces Vascular Permeability through Preferential Signaling via VEGF Receptor-1

Takahashi

Hattori

Iwamatsu

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Vascular endothelial growth factor (VEGF)/vascular permeability factor induces both angiogenesis and vascular permeability mainly through VEGF receptor (VEGFR)-2 activation. VEGF binds VEGFR-1 as well, but the importance of VEGFR-1 signaling in vascular permeability has been largely neglected. Here, we report the purification and characterization of a novel VEGF-like protein fromTrimeresurus flavoviridisHabu snake venom. The Habu snake has a venom-specific VEGF-like molecule,T. flavoviridissnake venom VEGF (TfsvVEGF), in addition to VEGF-A.TfsvVEGF has almost 10-fold less mitotic activity than VEGF165, a predominant isoform of human VEGF-A, but a similar effect on vascular permeability.TfsvVEGF bound VEGFR-1 and induced its autophosphorylation to almost the same extent as VEGF165, but bound VEGFR-2 weakly and induced its autophosphorylation almost 10-fold less effectively than VEGF165. This unique binding affinity for VEGFR-1 and VEGFR-2 leads to the vascular permeability-dominant activity ofTfsvVEGF. These results suggest that Habu snakes have acquired a highly purposive molecule for a toxin, which enhances the toxicity in envenomation without inducing effective angiogenesis and the following regeneration of damaged tissues, taking advantage of the difference in signaling properties involving VEGFR-1 and VEGFR-2 between vascular permeability and angiogenesis.TfsvVEGF is thus a potent inducing factor selective for vascular permeability through preferential signaling via VEGFR-1. These data strongly indicate the importance of VEGFR-1 signaling in vascular permeability.

show abstract

“…VEGF exerts its effects on endothelial cells by means of two tyrosine kinase receptors, the fms-like tyrosine kinase-1 (Flt-1; VEGFR-1) and fetal liver kinase-1 (Flk-1͞KDR; VEGFR-2) (7). VEGFR-2 is the dominant signaling receptor for many of VEGF's biological activities, including vascular permeability (8,9).…”

mentioning

confidence: 99%

Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site

Liu

Ren

Cooper

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

122

View full text Add to dashboard Cite

Vascular permeability plays a key role in a wide array of lifethreatening and sight-threatening diseases. Vascular endothelial growth factor can increase vascular permeability. Using a model system for nonproliferative diabetic retinopathy, we found that pigment epithelium-derived factor (PEDF) effectively abated vascular endothelial growth factor-induced vascular permeability. A 44-amino acid region of PEDF was sufficient to confer the antivasopermeability activity. Additionally, we identified four amino acids (glutamate-101, isoleucine-103, leucine-112, and serine-115) critical for this activity. PEDF, or a derivative, could potentially abate or restore vision loss from diabetic macular edema. Furthermore, PEDF may represent a superior therapeutic approach to sepsis-associated hypotension, nephrotic syndrome, and other sight-threatening and life-threatening diseases resulting from excessive vascular permeability.

show abstract

Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2)

Cited by 537 publications

References 50 publications

Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation

Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation

A Novel Snake Venom Vascular Endothelial Growth Factor (VEGF) Predominantly Induces Vascular Permeability through Preferential Signaling via VEGF Receptor-1

Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site

Contact Info

Product

Resources

About